Scientists
are now investigating the possibility of treating an aggressive form of brain
cancer, glioblastoma multiforme, not with typical chemotherapy, but with an
anti-viral vaccine. This may seem counterintuitive, especially since this type
of cancer has nothing to do with the Zika virus itself. However, this is
actually a very creative method for using the Zika virus’ unique properties to
help treat an extremely deadly cancer.
Glioblastoma
multiforme (GBM) is a brain cancer that develops from glial cells, which are
the support cells for the neurons that transmit our thoughts and movements. GBM
can appear on its own, or it can progress from lower grade brain tumors,
usually in adults age 45-70. This cancer is responsible for about 17% of all
tumors of the brain. It is the most invasive of its type, and usually results
in death 15 months after diagnosis, most often due to the recurrence of
secondary tumor.1 Current treatments include radiation therapy,
surgery to debulk the tumor, and treatment with the chemotherapy drug
temozolomide. Temozolomide is, unfortunately, associated with toxicity which
can cause acute liver injury in these patients.2 The biggest
problem, however is that it is very difficult to target the glioblastoma due to
its metastatic tendencies, which cause high rates of recurrence. There have been some attempts to address this
matter using nanoparticles, which helps in crossing the brain’s protective
barrier, the blood brain barrier, and helps increase the active life-span of
the drug.3 However, the issue of targeting only the cancerous cells
has still not been solved using this approach.
Zika
virus (ZIKV) is carried in mosquitos and infects humans when they are bitten by
the mosquito. When the infected person is a pregnant woman, the virus can
infect the fetus and cause the iconic microcephaly which is associated with
Zika infection. This decrease in the child’s head circumference arises from the
ability of ZIKV to induce early differentiation and apoptosis, or programmed
cell death, in human neural progenitor cells (HNPCs).4 The HNPCs are
stem cells which will later give rise to different cell types in the brain. The
virus preferentially infects these stem cells, leading to poor brain
development, which can present at birth or postnatally. The ability of ZIKV to
preferentially infect HNPCs is key for its use as a treatment for glioblastoma.
Within
glioblastomas are glial cells that reproduce at increased rates, similar to
those within HNPCs of the fetus. In contrast to healthy, differentiated adult
cells, these glioblastoma cells possess a poorly differentiated phenotype. This
makes Zika the ideal for attacking only the newly formed cancerous cells. A
live-attenuated vaccine allows the virus to stay viable, but does not allow it
to keep its virulence, which is what allows it to damage the host. In mouse
models, this approach has proven to be effective in both decreasing tumor size
and increasing post-infection life-span. As shown below, the Zika virus
live-attenuated vaccine (ZIKV-LAV) decreased growth of the tumors (A)(B)(D),
and increased survival time (C).6
Although
more animal testing is required before this approach is used in humans, it is
hopeful that the ZIKV-LAV could be used in combination with tumor debulking
surgery to reduce the number of recurrent metastases. This could be a novel
approach to address the problem of targeting therapy to such an invasive
cancer. As ZIK-LAV attacks the rapidly reproducing glioblastoma cells, they are
less able to spread themselves to further reaches of the brain, which is the
most dangerous part of this disease. If human trials are successful, we could
witness a total reversal in the survivability of glioblastoma.
1.
Rutka,
J. T. (2019). Glioblastoma Multiforme. Retrieved September 26, 2019, from https://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Glioblastoma-Multiforme.
2.
National Center for Biotechnology Information.
PubChem Database. Temozolomide, CID=5394, https://pubchem.ncbi.nlm.nih.gov/compound/Temozolomide (accessed on Sept. 26,
2019)
3.
Ozdemir-Kaynak,
E., Qutub, A. A., & Yesil-Celiktas, O. (2018, March 19). Advances in
Glioblastoma Multiforme Treatment: New Models for Nanoparticle Therapy.
Retrieved September 26, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868458/.
4.
Ferraris,
P., Cochet, M., Hamel, R., Gladwyn-Ng, I., Alfano, C., Diop, F., … Missé, D.
(2019, July 8). Zika virus differentially infects human neural progenitor cells
according to their state of differentiation and dysregulates neurogenesis
through the Notch pathway. Retrieved September 24, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691766/.
5.
Merfeld,
E., Ben-Avi, L., Kennon, M., & Cerveny, K. L. (2017, July). Potential
mechanisms of Zika-linked microcephaly. Retrieved September 26, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516183/.
6.
Chen,
Q., Wu, J., Ye, Q., Ma, F., Zhu, Q., Wu, Y., … Qin, C.-F. (2018, September 18).
Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine
Candidate. Retrieved September 23, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143740/.
By Andréa Gonzalez, Masters of Medical Sciences Student,
University of Kentucky
Great blog post! I am fascinated by virotherapy. It is extraordinary to think that scientists have found a way to treat cancer patients with viruses that when left alone have negative, and sometimes disastrous, effects. I am currently in a virology course that discusses virotherapy. Another example like the one mentioned in your blog that stood out to me was the use of Herpes Simplex Virus-1, which most people know as the cause for harmless cold sores. HSV-1 can actually be used to target cancer cells and to carry in genes that up-regulate the immune response to produce tumor antigens. The complexity of viruses is very intriguing but also very hopeful for future treatment of cancer patients. Great subject choice for your blog!
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ReplyDeleteUsing alternatives of treating types of brain cancer such as another virus sounds very confusing to most patients. In young developing children from 1-24 months of age has severe consequences to brain development to migrating and rapidly differentiating progenitor cells that are required to interact with glial cells, this interaction can be inhibited by cancer which disrupts neural progenitor cells from signaling and proliferating. which results into severely underdeveloped regions of the brain. Since radial glial cells are the primary transport for developing neurons to migrate and form neural complexes with other neurons. It is important to also consider the number of transcription factors and secondary small molecules being inhibited by inhibiting neural migration pathways in the SVZ/SGZ. emx2/pax6 are two very important for extensive development of cortical regions which appear to be down regulated and even mutated in certain cancers like glioblastomas. Regardless this new treatment may stop slow down degradation and enhance partially disrupted pathways to gain functionality but will have to happen immediately when this cancer is seen through brain imaging.
ReplyDeleteFascinating post! Virotherapy is a pretty incredible and exciting concept to think about, and genetically engineering these viruses to preferentially target cancerous cells seems to be a very hopeful candidate for the future of oncology. It's also interesting that your example of ZIKV successfully targeting GSCs in mouse models has been demonstrated at least more than once (Zhu, 2017), indicating some promising validity of the potential treatment.
ReplyDeleteHopefully in the near future this technology will be safe and efficacious to use in human patients, which is a very exciting thought. Thanks for sharing!
Zhu, Z. et al. (2017 Oct 2). Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med; 214(10):2843-2857. doi: 10.1084/jem.20171093. Epub 2017 Sep 5.
This is a very interesting topic and represents great promise for future cancer treatments. Currently, since this concept is in its infancy, it seems limited in that it represents a one-dimensional attack against cancer. As you stated, the promise lies in perfecting this technique and combining it with other therapies. Ideally, after developing this technology, we could use it to target any cell in the brain that is susceptible cancers; namely glioma stem cells, which are resistant to radiation and chemotherapy and capable of self-renewal and tumorigenicity. Combining this therapy with the reestablishment of healthy progenitor cells, so as not to create a deficit, should be our goal; kill the bad cells and replace them with good ones. Moreover, by using the cancer cells as your specific target, you could mark metastatic cells and prevent reoccurrence. In addition to this, we could use viral vectors and alter cancer genetics to promote immunogenic responses. Your post highlights a great example of the future of cancer immunotherapy, great job!
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ReplyDeleteAwesome post! Cancers, especially brain cancers, are an ever-changing problem for researchers and physicians. The theory of using a virus as a treatment for human diseases is brilliant due to the fact that viruses can pass through the blood brain barrier. The inability to cross the blood brain barrier is problematic for most treatments in many brain abnormalities including mitochondrial diseases and cancers. I have personally researched the use of a virus to be a vector for gene therapy. Knowing the fact that viruses can input its own genetic material into the host genome gives researchers a huge advantage for gene therapy. Unfortunately, there is never a “magic bullet” when it comes to disease treatment. One issue with using live viruses that can cross the BBB is the inability to control the virus once it’s administered. You have stated that the Zika virus attacks the glioblastoma cells because they have a poorly differentiated phenotype. I am wondering what this phenotype looks like to the virus. When brain cancer arises and tumors develop there are many other side effects of the tumor, including inflammation and scarring. Would this virus be able to specify the inflammation of neighboring non-cancerous cells from the cancer cells? Obviously, there is more research to be done, but the future of this treatment is very promising for oncology and mitochondrial metabolic disorders!
Wonderful! Your post is incredibly informative and I truly enjoyed reading it. It is fascinating to me that a connection was made that the Zika virus could infect the glioblastoma stem cells. I think this is really a case of science at its best: taking something negative like the Zika virus and using it to combat a devastating form of cancer. I love seeing the strides made in immunotherapy and virotherapy to treat cancer. Since the effectiveness of this vaccine for humans is still theoretical, I feel hopeful after reading your post. I know research is being done with cold viruses to destroy brain cancer, so I hope the Zika virus vaccine will prove to be beneficial. However, I will say that I am curious how opponents of vaccines will feel about this treatment if it is ultimately successful. I think effective alternative cancer treatments options should be available for patients who suffer from cancer so I am excited to see where this goes. Thank you for your post!
ReplyDeleteWow, great blog post. I had yet to hear about virotherapy as a treatment for GBM. Quite honestly,is interesting to me as cancer being the world's leading cause of death. It is miraculous the ability to take a modern spin on the old idea of viral infections and their ability to slow progression of cancer. I am intrigued that we as scientist and students are living in an era where modern day medicine is being transformed more and more. I look forward to being able to see the direction this goes in the near future.
ReplyDeleteRemarkable post, Andréa! I love that medicine is evolving to recycle a potent virus into a weapon that can target malignant cancer cells. What makes me curious is how they determine the potency of of the live-attenuated vaccine, or if there even is a way to customize this, so to speak. Every patient is different so I would guess that a complication could be that, while one "strength" of the vaccine may work to eradicate GBM in a group of patients, it could prove to be ineffective in another group. I would be interested to see if there is a way to determine and select for a certain virility and customize it based on specific patient needs, tumor stage and/or aggression.
ReplyDeleteGreat post Andréa! I love learning about the new ways we are finding to use vaccines in combating deadly diseases that have previously escaped us. I also love the use of the Zika virus for the poetic justice of it. It was only 2007 when the first large outbreak of this virus occurred on the island Yap. Since then it has found its way into countless news headlines and wrecked havoc in many countries. The ability for modern medicine to now use this virus to possibly bring an end to a disease that itself wrecks havoc is beautiful to me. It will never make up for the destruction it has and continues to have in some countries, but it will bring hope for those directly and indirectly connected to this form of cancer. This is just another example of why we need to continue heavily funding vaccine research.
ReplyDeleteJen Eccleston
ReplyDeleteScience is constantly evolving, and it amazes me how viral outbreaks can evoke such fear and yet here we are discussing how an intentional viral infection may one day be used to extend a cancer patient’s life. Interestingly, this concept of virotherapy is not as new as I thought.
As early as the 1800s people were beginning address the relationship between signs of cancer remission and viral infections. For instance, in the late 1800s, a 4-year-old boy with lymphatic leukemia suddenly went into remission days after being infected with chickenpox. Unfortunately, his remission was short-lived and the cancer quickly returned. Likewise, a woman diagnosed with a form of leukemia, also experienced signs of remission after what was believed to be an influenza infection. Many other cases such as these continued to spark people’s interest in the concepts behind virotherapy, and they became desperate to find answers. From there, studies began to evolve.
In the early 1950s, for example, West Nile Virus was being analyzed for its potential use for oncolytic purposes. However, what seems to be unlike the Zika virus live-attenuated vaccine, WNV proved to express high levels of toxicity and therefore would not be relevant for attacking specific cancer cells.
Reading the history as to how this research emerged is most fascinating to me. It is especially intriguing how this all coincidentally evolved from a patient falling into remission following a presumably unwanted viral infection, which has then led to the point where they are now working with a potential vaccine that holds promise for cancer patients.
Zhu, Zhe, et al., “Zika Virus Has Oncolytic Activity against Glioblastoma Stem Cells.” Journal of Experimental Medicine , 2 Oct. 2017, pp. 2843–2857.
Kelly, Elizabeth, and Stephen J Russell. “History of Oncolytic Viruses: Genesis to Genetic Engineering.” Molecular Therapy, vol. 15, no. 4, 2007, pp. 651–659.
Like the other responses, I too think this is a really interesting topic. When thinking about chemotherapy, you cannot ignore the side effects of the drug- infection due to neutropenia, neuropathy, mucositis, sometimes multi-organ damage, hair loss, ototoxicity, loss of taste, change in sexual function, anemia, fertility problems, etc. Sometimes too, people cannot even undergo chemotherapy because they too sick and chemotherapy would just be "too much." I am definitely not saying it is this simple, but at some point with some cancer diagnoses it's the idea of trying whatever you can to treat and alleviate the signs/symptoms of the cancer. So, after some more testing with oncolytic therapy, why not? When the patient is under so much distress from the cancer, why not try?
ReplyDeleteInteresting topic! I never thought about how scientists would ever use a vaccine as a treatment of another disease other than the one that they are created for. Especially for a brain cancer that is so deadly. It is amazing that the combination of the vaccine and tumor debulking surgery work well together. However as always, there are complications with any treatment. I wonder what the relationship is between the Zika virus and Glioblastoma multiforme that the vaccine works for both of them. This could be a foundation for new discoveries on cancer treatments. According to the Leukemia & Lymphoma Society, there are vaccines made for cancer, however they do not in the same way as vaccines work for measles and polio.
ReplyDeleteGknation. “Vaccine Therapy.” Leukemia and Lymphoma Society, 26 Feb. 2015, www.lls.org/treatment/types-of-treatment/vaccine-therapy.
This post was very interesting and this type of virotherapy is also being used in treating cancers and other disease. It was very interesting that Zika Virus was being used to help with treating GBM and how the proposed mechanism may help with treating GBM. The use of virotherapy has become a hot topic in recent years and has promising benefits for treating different diseases. The use of adenoviral vectors has become helpful in treating brain cancers because of its relative non-toxic and inability to integrate in the genome (1). Adenovirus has a double stranded DNA genome and various subtypes that can infect human cells (1). A particular adenovirus serotype-5 (Ad5) belong to subgroup C and uses the coxsackie and adenovirus receptor (CAR) to bind to surface receptor (1). The CAR ability to interact with virus base proteins and host surface integrins allow for adenovirus to internalize into the cells (1). This ability of adenovirus to go into tumor cells allows for reduction of CAR in tumor cells and in turn reduce GBM (1). This ability of adenovirus to do this helps with the reduction of GBM and be minimal in toxic side effects, while targeting specific tumor cells (1). There seems to be advantages to using virotherapy, but more research and specific attention to detail of how to deliver the virus, while only targeting specific cells will be a challenge that researchers need to better understand. These new emerging virotherapies allow for new promising ways and should be further studied by the scientific community.
ReplyDelete1. Nandi, Suvobroto, and Maciej S Lesniak. “Adenoviral virotherapy for malignant brain tumors.” Expert opinion on biological therapy vol. 9,6 (2009): 737-47. doi:10.1517/14712590902988451
I am honestly blown away by your topic. It is so compelling to think that viruses could be used as a treatment for cancers. Based on what I know about Parvovirus, I know that most canines are more susceptible to parvo early in life as their bodies are growing, and their cells are rapidly multiplying and dividing. In biochemistry, I also learned about how cancer cells rapidly multiply and divide because of their growth mechanisms. Taking these two things into account, I can see why one could make a connection between them. With further research, this could ultimately end up being an effective cure for cancer that we have been searching for. I think this would be a great area for scientists that are currently doing cancer research to really narrow in on. You did a great job with your blog post and you have made me so interested in this topic!
ReplyDeleteThis topic was interesting, it is amazing that researchers are using a virus like ZIKV to successfully treat glioblastomas. Sadly, I think a major obstacle researchers and physicians will face is not the development of this treatment but rather if they begin implementing this treatment in human patients. I remember in 2015 and 2016 it seemed that there was a Zika virus epidemic in North America and surrounding countries. The WHO even declared a Public Health Emergency of International Concern in 2016 because of numerous cases of microcephaly and Guillain–Barré syndrome caused by ZIKV. I think because of this many people associate the Zika virus with negative connotations which will make this treatment difficult to implement. With that being said, I do think this treatment is revolutionary and has the potential to save many lives, so it will be up to researchers to inform the general population in order to dispel their fears.
ReplyDeleteI always wondered why ZIKV seemed to have obvious neurologic effects on a developing fetus as opposed to all those infected. Your explanation of the mechanism used by ZIKV was very informative and helped me to understand that it could be viable for attacking newly formed neural cancer cells.
Cohen, Jon. (2016). Worries about brain damage in infants linked to Zika leads WHO to declare a public health emergency. Science. Science, 02/02/2016.
Hey Andréa, I found your blog to be incredibly interesting for several reasons. First, I had never heard of this intervention for glioblastomas before and it is quite ingenious. It’s remarkable to think that such a serious and terrifying virus could be altered and used to treat such a detrimental cancer. I find the idea that we, as scientists, can exploit the tools that a virus developed to treat a disease that is historically dangerous and difficult to target. One downside that I foresee, however, is that despite the specificity of the delivery of pharmaceutical agents to glial cells, healthy glial cells will be at risk even if other cell types are not. Glial cells are very important for normal neurologic health so future treatments should be aimed at increasing specificity to only cancer cells. I am also interested in this method because of the potential that it could have for other applications. It is an incredibly exciting concept that we could exploit viral targeting of specific cells to deliver a treatment to only that very specific or restricted population of cells.
ReplyDeleteI have to wonder, however, if many people will be willing to participate in trials for this drug assuming that it makes it to human trials. The zika virus is quite notorious and I do not believe that many people will be likely to willingly infect themselves with even an attenuated version. The average lay person may not understand the low risk of actual virulent infection and may opt for traditional but less effective treatments out of fear of the disease. Even still, many desperate people will try any treatment possible to cure cancer and regain their health so the number of patients willing to join the trial may surprise me when the time comes.
This was a very cool blog post, certainly one of the more creative approaches to treatment that I've seen. Initially, I found it hard to believe that infection of a virus could cause relief in a cancer, yet the way you displayed the information, it was easy to make the connection. I was curious to know if in the trials conducted with mice, were there any zika virus-type side effects that caused issue for the mice infected? Or was it so contained, that the virus only exerted its effects on the cancerous cells? This breakthrough, however, is huge, because to me it seems that several viruses mechanisms of action should be reviewed to see if there is potential for different types of cancer to be treated with this similar administration to those specific cells. I'd imagine that if the Zika Virus was targeting the cancer cells, solely, that patients going through this treatment would not see many of the classic side effects that chemotherapy treatments unfortunately have (i.e. vomiting, hair loss, etc.). While it was only briefly mentioned in your blog post, the point about using nanoparticles to cross the blood brain barrier for treatment really sparked an interest in me. It seems to me that if introducing the zika virus into a patient causes side effects, this nanoparticle technology should also be delved into experimentally. These nanoparticles can be programmed to bind solely to tumor cells to release the necessary drug. I don't necessarily see the zika virus being a cure (just prolonging life a little further), whereas these nanoparticles could provide us with a cure for cancer, specifically glioblastomas.
ReplyDelete-Alivia Larkin
Michael, J. S., Lee, B. S., Zhang, M., & Yu, J. S. (2018). Nanotechnology for Treatment of Glioblastoma Multiforme. Journal of translational internal medicine, 6(3), 128–133. doi:10.2478/jtim-2018-0025
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ReplyDeleteThis is a great blog with a very interesting topic! Despite chemotherapy being the long running treatment, it is very interesting to see all the new forms of treatments being discovered each day. Utilizing virotherapy is a very interesting treatment plan and I really like how you discussed it. Virotherapy will take many years and a significant amount of testing to be really put into action with human patients, however I think it is very likely to succeed. After reading this blog post, I became very interested in the topic, so I did some research. I found a research study recording the effects of using oncolytic virotherapy in the treatment of breast cancer patients. I will link it below; it has similar results that are very promising for the future of treatment!
ReplyDeletehttp://www.eurekaselect.com/165254/article
Samia M. O`Bryan and J. Michael Mathis*, “Oncolytic Virotherapy for Breast Cancer Treatment”, Current Gene Therapy (2018) 18: 192. https://doi.org/10.2174/1566523218666180910163805
This is so interesting! I’m currently in an entomology/epidemiology class relating to human health and disease, so Zika has been a major discussion. I would have never thought that a vaccine such as this could have other benefits. While the vaccine is not virulent, it does make me wonder about the ethics and safety behind using such a detrimental virus as a solution. Don’t get me wrong, I am a HUGE advocate for vaccines and believe that they are essential to our societies safety. Live vaccines have been used to successfully eliminate threats from certain illnesses such as the measles and chickenpox. However, I have always been aware of the fact that live vaccines can be detrimental to individuals with a weakened immune system. I would definitely like to look into the impacts on the immune system that the use of a live vaccine may have in patients with conditions such as cancer. Which usually requires treatments that have a high impact on the immune system.
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